Since the Women's Health Initiative found that estrogen
treatment posed an increased risk for developing breast cancer,
physicians and patients have become wary of hormone replacement therapy.
Prescription use of estrogen and "progesterone" medications
such as Premarin and Prempro have dramatically declined since 2003. Many
patients have opted to avoid hormone replacement, attempting to control
menopausal symptoms with nonestrogen medications such as
antidepressants. While estrogen treatment with conjugated equine
estrogen such as Premarin demonstrably provided support for
osteoporosis, it failed to reduce risk of cardiovascular disease, a
claim touted in the past few decades. Understandably, physicians and
patients concerned about increasing breast cancer risks have decided
that lower estrogen and progesterone levels are a natural part of the
aging process. Much of the promise of menopausal hormone replacement
acclaimed in the 1980s has lost its appeal.

[ILLUSTRATION OMITTED]

In the years following the Women's Health Initiative, Suzanne
Somers's best-selling books argued that estrogen replacement should
still be a consideration in treating menopause and the aging process.
Her use of "bioidentical" hormones raised eyebrows because she
was using relatively high doses of estrogen after being diagnosed with
breast cancer. Somers argued that, compared with conventional hormone
replacement, bioidentical hormones are structurally identical to the
body's estrogen and progesterone. Other prescription estrogen and
progesterone had been chemically modified and did not match human
hormones. Bioidentical hormone replacement derived from plant sources,
prescribed by a minority of physicians for the past two to three
decades, offered a distinct alternative to horse-derived estrogens and
chemically modified progesterone. The question remained whether the
benefits from using bioidentical therapy outweighed risks for developing
breast cancer.

According to Jonathan Wright, MD, and Lane Lenard, PhD, in their
updated edition of Stay Young & Sexy with BioIdentical Hormone
Replacement: The Science Explained (Smart Publications, 2010), the
answer is an unqualified "yes." The major bioidentical
estrogens, estrone, estradiol, and estriol, are generally prescribed
with progesterone in lower physiologic doses meant to mimic the normal
female cycle. Wright explains that estrogen stimulation of alpha
receptors tends to increase cell proliferation, while beta receptors
tend to decrease it. Estradiol stimulates alpha and beta receptors
equally; estrone stimulates the alpha receptor five times more than the
beta receptor, meaning that estrone tends to provoke much greater cell
proliferation than estradiol. Estriol, on the other hand, tends to
stimulate beta receptors three times more than alpha receptors, greatly
decreasing cell proliferation. Given that estrone and estradiol
stimulate cell proliferation, increasing the risk for breast cancer,
estriol is the predominant estrogen prescribed, to lessen cell
proliferation activity.

Much of Wright's thinking is based on the work of Dr. Harry
Lemon, who headed the division of gynecologic oncology at the University
of Nebraska in the 1970s. Lemon observed that estriol was capable of
competing with estradiol and estrone for occupation of estrogen receptor
sites. (1) He hypothesized that if estriol was not present in adequate
quantities and estrone and estradiol were relatively high, estrogen
receptors would be stimulated and the risk of breast cell proliferation
would be greatly increased. Lemon derived an estrogen quotient defined
as: estriol/(estrone + estradiol) = estrogen quotient. If this ratio of
estriol to estrone and estradiol exceeded 1.2, the woman would have a
lower risk for developing breast cancer; if the ratio was less than 0.5,
the woman had a significantly higher risk for developing cancer. Wright
recommends that women who are prescribed bioidentical hormone
replacement therapy have a urinary hormone screen of estriol, estrone,
and estradiol to measure the estrogen quotient. Those women with lower
estrogen quotients would then be able to have their prescriptions
modified to increase their relatively low estriol levels.

The French MISSION study on hormone replacement therapy reported in
2007 had very different results than the Women's Health Initiative.
(2) The study compared the incidence of breast cancer of women who had
been treated with estrogen during the past five years with that in women
who had received no hormone treatment. There was no increase in breast
cancer incidence in the estrogen group compared with the nonestrogen
one, despite the fact that the average use of estrogen exceeded eight
years. How could these results be so different from the Women's
Health Initiative? According to the French researchers, unlike in the
American study, most of the women did not use conjugated equine
estrogens and synthetic progestogens. Instead they were prescribed
bioidentical topical estradiol and progesterone.

Unfortunately, the MISSION study did not employ estriol, and there
are no large studies employing estriol hormone replacement. However, the
evidence and theory largely supports including estriol in bioidentical
hormone prescribing. Wright and Lenard's text offers further
compelling information on estriol and other hormones, including best
means to prescribe and monitor them. Patients and physicians are well
served to be cautious in using hormone replacement, but bioidentical
hormone therapy appears to be a far lower risk than the horse-derived
hormone replacement used in the past three decades.

Jonathan Collin, MD

Notes

(1.) Lemon HM. Pathophysiologic considerations in the treatment of
menopausal patients with oestrogens; the role of oestriol in the
prevention of mammary carcinoma. Acta Endocrinol. Supple (Copenh).
1980;233;17-27.